Neutrophil heterogeneity in anti-neutrophil cytoplasm antibody associated vasculitis

ANCA相关性血管炎(AAV)是一种自身免疫性疾病。当我们的免疫系统--通常抵抗感染的免疫系统--将我们身体的某些部分识别为“异体”而不是“自我”时，就会发生自身免疫。在AAV中，这会导致小血管发炎，称为脉管炎。身体许多不同部位的血管都会受到影响，包括肠道、皮肤、神经、肺和肾脏。这种情况通常会危及生命，因为肺部严重出血或肾脏发炎。即使接受治疗，患者也可能发展为肾衰竭，需要长期的透析治疗。我们知道中性粒细胞(一种白细胞)在AAV中非常重要。AAV患者会产生抗体，称为ANCA，可以激活中性粒细胞，导致他们损伤血管。直到最近，中性粒细胞还被认为是一种简单的细胞类型，寿命短，唯一的目的是抵抗感染。然而，最近的研究表明，并不是所有的中性粒细胞都是相同的，可能有许多不同的类型，具有不同的功能和用途。在我的初步研究中，我发现未经治疗的AAV患者血液中有不同类型的中性粒细胞，与健康人的中性粒细胞相比，它们的外观和行为都不同。然而，目前尚不清楚是什么原因导致AAV患者体内这些细胞的发育，也不清楚它们是否在导致疾病中发挥了重要作用。AAV是一种终生疾病，这种疾病及其治疗往往会导致严重的并发症，如糖尿病、感染、癌症或心脏病。这种情况对受影响患者的生活质量有重大影响，复发(成功治疗后疾病复发)是一个主要问题。患者已经认识到，他们感觉像是站在一把刀的边缘，夹在持续的免疫抑制治疗(有潜在的严重风险，如感染或癌症)和随着停止治疗而复发的风险之间。一些AAV患者比其他患者更有可能复发，尽管我们不完全了解原因，但部分原因可能是不同类型的抗体(ANCA)导致的疾病。迫切需要对AAV进行更具体的治疗，并更好地了解为什么一些患者复发，另一些患者不复发。我认为，中性粒细胞亚型的差异可能解释了不同ANCA的AAV患者病情表现不同的原因。在这次的团契中，我计划全面了解AAV中存在的不同类型的中性粒细胞，并将使用几种方法来完成这一任务，包括分析基因、细胞表面的蛋白质和物理特征(例如，大小、形状、僵硬)，因为越坚硬的细胞更有可能卡在小血管中并损伤小血管。我将从血液中分离患者的中性粒细胞，并研究它们的功能是否与健康的中性粒细胞不同，重点是细胞损伤血管的能力。使用组织(患者进行活检诊断脉管炎时的剩余物)，我将使用一种新技术，使我能够观察组织中存在的中性粒细胞的基因构成。这将使我能够看到我在血液中识别的相同细胞是否存在于脉管炎的组织炎症部位。最后，使用血管炎的大鼠模型，我将研究直接以中性粒细胞为靶点是否可能是治疗血管炎的有效方法。我最初的实验将专注于通过使中性粒细胞变得更柔软来防止中性粒细胞滞留在组织中。我的目标是，通过显著增加我们对患者为什么患AAV以及为什么患者之间的病情表现不同的理解，我们将能够针对这些细胞，为患者提供更好的治疗，使其针对他们所患的AAV类型。我希望这项工作将直接导致临床研究，有可能直接造福于患者。

ANCA associated vasculitis (AAV) is a type of autoimmune disease. Autoimmunity occurs when our immune system, which normally fights infection, instead recognises parts of our own bodies as 'foreign' instead of 'self'. In AAV this leads to inflammation of small blood vessels, known as vasculitis. Blood vessels in many different parts of the body can be affected, including the gut, skin, nerves, lung and kidneys. The condition is often life-threatening, due to severe bleeding in the lungs or inflammation of the kidneys. Even with treatment, patients may develop kidney failure requiring long-term dialysis treatment. We know that neutrophils (a type of white blood cell) are very important in AAV. Patients with AAV make antibodies, called ANCA, that activate neutrophils leading them to damage blood vessels. Until recently neutrophils were thought of as a simple cell type with a short life span and the sole purpose of fighting infection. However, recent research has shown that not all neutrophils are the same and there may be many different types with different functions and purpose. In my preliminary studies, I have found different types of neutrophil in the blood of patients with untreated AAV, that look and behave differently compared to neutrophils from healthy individuals. It is not clear, however, what causes these cells to develop in patients with AAV or if they have an important role in causing the disease. AAV is a life-long condition and both the disease and its treatment often lead to the development of significant complications such as diabetes, infection, cancer or heart disease. The condition has a significant impact on the quality of life of affected patients and relapse (return of the disease after successful treatment) is a major concern. Patients have identified that it feels like they are on a 'knife-edge', caught between continuing immunosuppressive treatment (with potentially serious risks such as infection or cancer) versus risk of relapse with weaning of treatment. Some patients with AAV are more likely to relapse than others and although we do not fully understand why, it may in part be due to different types of antibodies (ANCA) causing disease. There is an urgent need for more specific treatments for AAV and for a better understanding of why some patients relapse and others do not. I suggest that differences in neutrophil subtypes may explain why the condition behaves differently between patients with AAV with different ANCA.In this Fellowship, I plan to fully understand the different types of neutrophil present in AAV and will use several methods to do this, including analysis of genes, proteins on the cell surface, and physical features (e.g. size, shape, stiffness) as cells which are stiffer are more likely to become lodged in and damage small blood vessels. I will isolate patient neutrophils from blood and investigate if they function differently from healthy neutrophils focussing on the capacity of the cells to damage blood vessels. Using tissue (leftover from when patients have a biopsy to diagnose vasculitis) I will use a new technique which allows me to look at the genetic make-up of neutrophils present in the tissues. This will enable me to see if the same cells I identify in blood are present at tissue sites of inflammation in vasculitis. Finally using a rat model of vasculitis I will investigate whether targeting neutrophils directly might be an effective treatment for vasculitis. My initial experiments will focus on preventing neutrophils becoming lodged in tissues by making them softer. My aim is that by significantly increasing our understanding of why patients get AAV and why the condition behaves differently between patients we will be able to target these cells leading to better treatments for patients which are 'personalised' to the type of AAV they have. I hope that this work will directly lead on to clinical studies with the potential for direct benefit to patients.